rs34134242

chr18-10672785-T-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001378183.1(PIEZO2):c.8250A>T(p.Gly2750=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 1,614,062 control chromosomes in the GnomAD database, including 171 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (16 hom., cov: 32)
  • Exomes 𝑓: 0.015 (155 hom.)
• Consequence: PIEZO2 NM_001378183.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0410

Genes affected

PIEZO2 (HGNC:26270): (piezo type mechanosensitive ion channel component 2) The protein encoded by this gene contains more than thirty transmembrane domains and likely functions as part of mechanically-activated (MA) cation channels. These channels serve to connect mechanical forces to biological signals. The encoded protein quickly adapts MA currents in somatosensory neurons. Defects in this gene are a cause of type 5 distal arthrogryposis. Several alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known. [provided by RefSeq, Feb 2014]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 18-10672785-T-A is Benign according to our data. Variant chr18-10672785-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 261531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-10672785-T-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.041 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0118 (1794/152314) while in subpopulation AMR AF= 0.0245 (374/15292). AF 95% confidence interval is 0.0224. There are 16 homozygotes in gnomad4. There are 880 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 16 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIEZO2	NM_001378183.1	c.8250A>T	p.Gly2750=	synonymous_variant	55/56	ENST00000674853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIEZO2	ENST00000674853.1	c.8250A>T	p.Gly2750=	synonymous_variant	55/56		NM_001378183.1

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1793 AN: 152196 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00297

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0245

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0118

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0161

Gnomad OTH AF: 0.0220

GnomAD3 exomes AF: 0.0107 AC: 2681 AN: 251406 Hom.: 23 AF XY: 0.0108 AC XY: 1467 AN XY: 135874

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.0129

Gnomad ASJ exome AF: 0.00943

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.0104

Gnomad NFE exome AF: 0.0155

Gnomad OTH exome AF: 0.0174

GnomAD4 exome AF: 0.0150 AC: 21874 AN: 1461748 Hom.: 155 Cov.: 31 AF XY: 0.0145 AC XY: 10551 AN XY: 727178

Gnomad4 AFR exome AF: 0.00248

Gnomad4 AMR exome AF: 0.0146

Gnomad4 ASJ exome AF: 0.0104

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.0103

Gnomad4 NFE exome AF: 0.0174

Gnomad4 OTH exome AF: 0.0151

GnomAD4 genome AF: 0.0118 AC: 1794 AN: 152314 Hom.: 16 Cov.: 32 AF XY: 0.0118 AC XY: 880 AN XY: 74492

Gnomad4 AFR AF: 0.00296

Gnomad4 AMR AF: 0.0245

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0118

Gnomad4 NFE AF: 0.0161

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.0143 Hom.: 8

Bravo AF: 0.0137

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0167

EpiControl AF: 0.0171

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2020	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	7.1
Dann	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs34134242; hg19: chr18-10672782;